Selected 2017 Publications

CX3CL1 and IL-15 Promote CD8 T cell chemoattraction in HIV and in atherosclerosis.

Panigrahi S, Chen B, Fang M, Potashnikova D, Komissarov AA, Lebedeva A, Michaelson GM, Wyrick JM, Morris SR, Sieg SF, Paiardini M, Villinger FJ, Harth K, Kashyap VS, Cameron MJ, Cameron CM, Vasilieva E, Margolis L, Younes SA, Funderburg NT, Zidar DA, Lederman MM, Freeman ML.

PLoS Pathog. 2020 Sep;16(9):e1008885. doi: PPATHOGENS-D-20-00809. Epub.

Abstract: Atherosclerotic cardiovascular disease (ASCVD) remains an important cause of morbidity in the general population and risk for ASCVD is increased approximately 2-fold in persons living with HIV infection (PLWH). This risk is linked to elevated CD8 T cell counts that are abundant in atherosclerotic plaques and have been implicated in disease pathogenesis yet the mechanisms driving T cell recruitment to and activation within plaques are poorly defined. Here we investigated the role of CD8 T cells in atherosclerosis in a non-human primate model of HIV infection and in the HIV-uninfected elderly; we sought to identify factors that promote the activation, function, and recruitment to endothelium of CX3CR1+ CD8 T cells. We measured elevated expression of CX3CL1 and IL-15, and increased CD8 T cell numbers in the aortas of rhesus macaques infected with SIV or SHIV, and demonstrated similar findings in atherosclerotic vessels of HIV-uninfected humans. We found that recombinant TNF enhanced the production and release of CX3CL1 and bioactive IL-15 from aortic endothelial cells, but not from aortic smooth muscle cells. IL-15 in turn promoted CX3CR1 surface expression on and TNF synthesis by CD8 T cells, and IL-15-treated CD8 T cells exhibited enhanced CX3CL1-dependent chemoattraction toward endothelial cells in vitro. Finally, we show that CD8 T cells in human atherosclerotic plaques have an activated, resident phenotype consistent with in vivo IL-15 and CX3CL1 exposure. In this report, we define a novel model of CD8 T cell involvement in atherosclerosis whereby CX3CL1 and IL-15 operate in tandem within the vascular endothelium to promote infiltration by activated CX3CR1+ memory CD8 T cells that drive further endothelial activation via TNF. We propose that these interactions are prevalent in aging and in PLWH, populations where circulating activated CX3CR1+ CD8 T cell numbers are often expanded. © PLoS Pathogens.

Pathogenesis of Aging and Age-related Comorbidities in People with HIV: Highlights from the HIV ACTION Workshop.

Gabuzda D, Jamieson BD, Collman RG, Lederman MM, Burdo TH, Deeks SG, Dittmer DP, Fox HS, Funderburg NT, Pahwa SG, Pandrea I, Wilson CC, Hunt PW.

Pathog Immun 2020 ;5(1):143-174. doi: pai.v5i1.365. Epub.

Abstract: People with HIV (PWH) experience accentuated biological aging, as defined by markers of inflammation, immune dysfunction, and the epigenetic clock. They also have an elevated risk of multiple age-associated comorbidities. To discuss current knowledge, research gaps, and priorities in aging and age-related comorbidities in treated HIV infection, the NIH program staff organized a workshop held in Bethesda, Maryland in September 2019. This review article describes highlights of discussions led by the Pathogenesis/Basic Science Research working group that focused on three high priority topics: immunopathogenesis; the microbiome/virome; and aging and senescence. We summarize knowledge in these fields and describe key questions for research on the pathogenesis of aging and age-related comorbidities in PWH. Understanding the drivers and mechanisms underlying accentuated biological aging is a high priority that will help identify potential therapeutic targets to improve healthspan in older PWH. © Pathogens & Immunity.

SARS-CoV-2 and ACE2: The biology and clinical data settling the ARB and ACEI controversy.

Chung MK, Karnik S, Saef J, Bergmann C, Barnard J, Lederman MM, Tilton J, Cheng F, Harding CV, Young JB, Mehta N, Cameron SJ, McCrae KR, Schmaier AH, Smith JD, Kalra A, Gebreselassie SK, Thomas G, Hawkins ES, Svensson LG.

EBioMedicine 2020 Aug;58():102907. doi: 10.1016/j.ebiom.2020.102907. Epub.

Abstract: SARS-CoV-2 enters cells by binding of its spike protein to angiotensin-converting enzyme 2 (ACE2). Angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin II receptor blockers (ARBs) have been reported to increase ACE2 expression in animal models, and worse outcomes are reported in patients with co-morbidities commonly treated with these agents, leading to controversy during the COVID-19 pandemic over whether these drugs might be helpful or harmful. © EBioMedicine.

Massive release of CD9+ microvesicles in HIV infection, regardless of virologic control.

Poveda E, Tabernilla A, Fitzgerald W, Salgado-Barreira Á, Grandal M, Pérez A, Mariño A, Álvarez H, Valcarce N, González-García J, Bernardino JI, Gutierrez F, Fujioka H, Crespo M, Ruiz-Mateos E, Margolis L, Lederman MM, Freeman ML, .

J. Infect. Dis. 2020 Jun;():. doi: 10.1093/infdis/jiaa375. Epub.

Abstract: The role of extracellular vesicles (EVs) in HIV pathogenesis is unknown. We examine the cellular origin of plasma microvesicles (MVs), a type of ectocytosis-derived EV, the presence of mitochondria in MVs, and their relationship to circulating cell-free mitochondrial DNA (ccf-mtDNA) in HIV-infected patients and controls. © The Journal Of Infectious Diseases.

Antiretroviral Treatment for HIV Elite Controllers?

Ruiz-Mateos E, Poveda E, Lederman MM.

Pathog Immun 2020 ;5(1):121-133. doi: pai.v5i1.364. Epub.

Abstract: In most HIV-infected persons, the natural history of untreated infection is one of sustained viremia, progressive CD4 T cell depletion with resultant morbidity and mortality. The advent of effective combination antiretroviral therapy (ART) that controls HIV replication has altered this landscape dramatically. Yet a rare population of HIV-infected persons-elite controllers (EC)-can control HIV replication such that plasma levels of virus are "undetectable" without ART. The EC phenotype is heterogeneous, with some subjects durably controlling the virus-persistent elite controllers-and some eventually losing viral control-transient elite controllers. Overall, EC tend to have robust HIV-specific T cell responses and in some cases, mainly in transient elite controllers, elevated activation and inflammation indices that diminish with ART suggesting that endogenous defenses against this persistent pathogen come at the cost of heightened activation/inflammation. A limited data set suggests that cardiovascular disease risk as well as the occur-rence of other morbid events may be greater in the overall EC population than in treated HIV infection. ART in EC decreases activation indices but does not appear to increase circulating CD4 T cell numbers nor do we know if it alters clinical outcomes. Thus, it is difficult to recommend or discourage a decision to start ART in the EC population but the authors lean toward treatment particularly in those EC whose activation indices are high and those who are progressively losing circulating CD4 T cell numbers. Biomarkers that can reliably predict loss of virologic control and immune failure are needed. © Pathogens & Immunity.

'Rinse and Replace': Boosting T Cell Turnover To Reduce HIV-1 Reservoirs.

Grossman Z, Singh NJ, Simonetti FR, Lederman MM, Douek DC, Deeks SG, .

Trends Immunol. 2020 Jun;41(6):466-480. doi: 10.1016/ Epub.

Abstract: Latent HIV-1 persists indefinitely during antiretroviral therapy (ART) as an integrated silent genome in long-lived memory CD4 T cells. In untreated infections, immune activation increases the turnover of intrinsically long-lived provirus-containing CD4 T cells. Those are 'washed out' as a result of their activation, which when coupled to viral protein expression can facilitate local inflammation and recruitment of uninfected cells to activation sites, causing latently infected cells to compete for survival. De novo infection can counter this washout. During ART, inflammation and CD4 T cell activation wane, resulting in reduced cell turnover and a persistent reservoir. We propose accelerating reservoir washout during ART by triggering sequential waves of polyclonal CD4 T cell activation while simultaneously enhancing virus protein expression. Reservoir reduction as an adjunct to other therapies might achieve lifelong viral control. © Trends In Immunology.

Inflammescent CX3CR1+CD57+CD8+ T cells are generated and expanded by IL-15.

Morris SR, Chen B, Mudd JC, Panigrahi S, Shive CL, Sieg SF, Cameron CM, Zidar DA, Funderburg NT, Younes SA, Rodriguez B, Gianella S, Lederman MM, Freeman ML.

JCI Insight 2020 Jun;5(11):. doi: 10.1172/jci.insight.132963. Epub.

Abstract: HIV infection is associated with an increase in the proportion of activated CD8+ memory T cells (Tmem) that express CX3CR1, but how these cells are generated and maintained in vivo is unclear. We demonstrate that increased CX3CR1 expression on CD8+ Tmem in people living with HIV (PLWH) is dependent on coinfection with human CMV, and CX3CR1+CD8+ Tmem are enriched for a putatively immunosenescent CD57+CD28- phenotype. The cytokine IL-15 promotes the phenotype, survival, and proliferation of CX3CR1+CD57+CD8+ Tmem in vitro, whereas T cell receptor stimulation leads to their death. IL-15-driven survival is dependent on STAT5 and Bcl-2 activity, and IL-15-induced proliferation requires STAT5 and mTORC1. Thus, we identify mechanistic pathways that could explain how "inflammescent" CX3CR1+CD57+ CD8+ Tmem dominate the overall memory T cell pool in CMV-seropositive PLWH and that support reevaluation of immune senescence as a nonproliferative dead end. © JCI Insight.

Presence of asymptomatic cytomegalovirus and Epstein--Barr virus DNA in blood of persons with HIV starting antiretroviral therapy is associated with non-AIDS clinical events.

Gianella S, Moser C, Vitomirov A, McKhann A, Layman L, Scott B, Caballero G, Lada S, Bosch RJ, Hoenigl M, Lurain N, Landay A, Lederman MM, Hunt PW, Smith D.

AIDS 2020 05;34(6):849-857. doi: 00002030-202005010-00005. Epub.

Abstract: Even with antiretroviral therapy (ART), persons with HIV (PWH) experience increased morbidity and mortality. Cytomegalovirus (CMV) and Epstein--Barr virus (EBV) co-infections likely exacerbate inflammatory-related diseases. © AIDS (London, England).

Cytomegalovirus Coinfection Is Associated with Increased Vascular-Homing CD57 CD4 T Cells in HIV Infection.

Chen B, Morris SR, Panigrahi S, Michaelson GM, Wyrick JM, Komissarov AA, Potashnikova D, Lebedeva A, Younes SA, Harth K, Kashyap VS, Vasilieva E, Margolis L, Zidar DA, Sieg SF, Shive CL, Funderburg NT, Gianella S, Lederman MM, Freeman ML.

J. Immunol. 2020 May;204(10):2722-2733. doi: 10.4049/jimmunol.1900734. Epub.

Abstract: Cytotoxic CD4 T cells are linked to cardiovascular morbidities and accumulate in both HIV and CMV infections, both of which are associated with increased risk of cardiovascular disease (CVD). In this study, we identify CMV coinfection as a major driver of the cytotoxic phenotype, characterized by elevated CD57 expression and reduced CD28 expression, in circulating CD4 T cells from people living with HIV infection, and investigate potential mechanisms linking this cell population to CVD. We find that human CD57 CD4 T cells express high levels of the costimulatory receptor CD2 and that CD2/LFA-3 costimulation results in a more robust and polyfunctional effector response to TCR signals, compared with CD28-mediated costimulation. CD57 CD4 T cells also express the vascular endothelium-homing receptor CX3CR1 and migrate toward CX3CL1-expressing endothelial cells in vitro. IL-15 promotes the cytotoxic phenotype, elevates CX3CR1 expression, and enhances the trafficking of CD57 CD4 T cells to endothelium and may therefore be important in linking these cells to cardiovascular complications. Finally, we demonstrate the presence of activated CD57 CD4 T cells and expression of CX3CL1 and LFA-3 in atherosclerotic plaque tissues from HIV-uninfected donors. Our findings are consistent with a model in which cytotoxic CD4 T cells contribute to CVD in HIV/CMV coinfection and in atherosclerosis via CX3CR1-mediated trafficking and CD2/LFA-3-mediated costimulation. This study identifies several targets for therapeutic interventions and may help bridge the gap in understanding how CMV infection and immunity are linked to increased cardiovascular risk in people living with HIV infection. © Journal Of Immunology (Baltimore, Md. : 1950).

Compulsory Immunization Protects Against Infection: What Law and Society Can Do.

Mehlman MJ, Lederman MM.

Pathog Immun 2020 ;5(1):1-7. doi: pai.v5i1.344. Epub.

Abstract: Since their broad implementation, immunizations have decreased morbidity and mortality due to a number of serious infectious diseases. In recent years, exaggerated concerns about the safety of immunizations have resulted in decreased immunization coverage in many regions and epidemic outbreaks of serious transmissible diseases - most particularly measles. This commentary reviews the legal justification for compulsory immunization and the ethical justification for civil incentives to assure compliance with immunization practices. © Pathogens & Immunity.